1. Field of the Invention
The Invention relates to a method for preparing a crystalline polymorph of 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(2-tetrahydrofuroyl)-piperazine -monohydrochloride, hereinafter abbreviated as terazosin hydrochloride.
2. Description of Related Art
The compound 1-(4-amino-6,7-dimethoxy-2-guinazolinyl)-4-(2-tetrahydrofuroyl)-piperazine is generally known under the name terazosin. For the monohydrochloride of this compound there have been known to exist a plurality of anhydrous crystalline modifications (polymorphs) as well as a crystalline dihydrate form and a crystalline adduct with methanol. The compound and the different polymorphs thereof are suitable for pharmaceutical use, for example for the treatment of hypertension.
The Japanese Laid-Open Unexamined Patent Application 05-78352 SUMIKA describes a plurality of crystalline forms of terazosin hydrochloride and the ways of preparing them. One crystalline polymorph, denoted as type A-2 in that document, is characterized by an X-ray powder diffraction pattern having characteristic peaks at 7.degree., 12.degree., 20.3.degree. and is believed to be identical to the product of the method according to the present Invention. According to the prior art document this polymorph is prepared as follows: First the free terazosin base is prepared. This is converted into the crystalline adduct of the hydrochloride thereof with methanol. Thereafter, the methanol included in the crystal is removed by drying, which necessitates temperatures around 110.degree. C. One obtains a substantially methanol free compound, which is very hygroscopic. This is further treated with ethanol or mixtures of ethanol and methylene chloride for obtaining the desired crystalline polymorph which is substantially not hygroscopic.
U.S. Pat. No. 5,412,095 and EP 0 683 167 disclose methods for obtaining other crystalline forms of terazosin-hydrochloride. One of the methods described therein also comprises the treatment of the adduct of terazosin-hydrochloride and methanol in suspension in a solvent such as ethanol. This prior art treatment, however, is performed at a comparatively low temperature (50.degree. C.) and for a comparatively short time (10 minutes or 30 minutes), and the product is a crystalline polymorph, designated as Form III in this document, which differs from the polymorph according to the Invention with respect to its X-ray pattern and other parameters.
The crystalline polymorph to which the present Invention relates is also described in EP-0 708 104 A1 which is not prepublished, and it is designated there as "Form IV". The method of preparation proposed in this document starts from N-(2-tetrahydrofuroyl)-piperazine (the preparation of which by hydrogenation of N-(2-furoyl)-piperazine has already been known from U.S. Pat. No. 4,026,894), which is then coupled with 4-amino-2-chloro-6,7-dimethoxy-quinazoline, which requires a treatment including boiling for several hours in a solvent having a high boiling temperature, whereby terazosin hydrochloride in the crystalline Form IV is obtained. This product is then converted into the dihydrate and dried. A drawback of this method consists in requiring several hours of boiling in a solvent having a high boiling temperature (for example methoxyethanol which is objectionable for health reasons) whereby impurities are necessarily formed and an undesirable dark color is obtained. Thus, the crystalline Form IV is not obtained in the optimal purity which is desired for pharmacological uses, but requires further treatment (forming of dihydrate), which causes a purification, including a treatment with diatomaceous earth.
Other crystalline polymorphs of terazosin hydrochloride and methods for their preparation are disclosed in U.S. Pat. Nos. 5,294,615, 5,362,730 and 5,412,095 and are referred therein as Form II and Form III, respectively, and are characterized by the characteristic peaks of the X-ray powder diffraction patterns thereof.